Sunday, May 23, 2021

Noncoding “Junk” DNA Is Important for Limb Formation


Noncoding “Junk” DNA Is Important for Limb Formation
Casey Luskin

Image credit: Schäferle via Pixabay.

A 2021 article in Nature, “Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator,” reports important new functions for non-coding or “junk” DNA that underlie limb formation. Before we get to the paper itself, consider a description of it on the Proceedings of the National Academy of Sciences “Journal Club” blog. The latter describes the research in terms that sound like they could have come directly from an intelligent design source: 

Genes that code for proteins make up only about 2% of the human genome. Many researchers once dismissed the other 98% of the genome as “junk DNA,” but geneticists now know these noncoding regions help to regulate the activity of the 20,000 or so protein-coding genes identified.

A new study in Nature underscores just how important noncoding DNA can be for human development. The authors show that deletions in a noncoding region of DNA on chromosome 2 cause severe congenital limb abnormalities. This is the first time a human disease has been definitively linked to mutations in noncoding DNA, says lead author Stefan Mundlos, head of the development and disease research group at the Max Planck Institute for Molecular Genetics in Berlin, Germany.

“Severe Congenital Limb Malformation” 

The technical paper in Nature describes the research. The investigators examined the chromosomes of people who had naturally occurring limb malformation, and found that these people had deletions of DNA encoding long non-coding RNA sequences (lncRNAs) from human chromosome 2. They deleted corresponding DNA sequences in mice and found similar “severe congenital limb malformation,” suggesting these lncRNA sequences are functionally important:

Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27–63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. 

In the discussion, the article explains how important it is that we seek to understand the key functions of non-coding DNA sequences that encode lncRNAs:

In the era of whole-genome sequencing, the findings described here underscore the need for a systematic annotation and functional characterization of lncRNA loci to interpret and classify non-coding genetic variants. They highlight the importance of elucidating the complex diversity of lncRNA modes of action to assess their role in organ development and disease.

Over 130,000 Functional “Junk DNA” Elements!

So just how are we progressing in the task of determining the functions of non-coding DNA elements? Some defenders of evolutionary orthodoxy would have us believe that we’ve only found a handful of non-coding DNA sequences that have function — exceptions to the rule that non-coding DNA is usually useless junk. Another 2021 article in Nature shows why it’s no longer tenable for evolutionists to hide behind such an argument from ignorance. The article explains that over 130,000 functional “genomic elements, previously called junk DNA” have now been discovered, highlighting how important these “junk” segments have turned out to be:

[I]t is now appreciated that the majority of functional sequences in the human genome do not encode proteins. Rather, elements such as long non-coding RNAs, promoters, enhancers and countless gene-regulatory motifs work together to bring the genome to life. Variation in these regions does not alter proteins, but it can perturb the networks governing protein expression With the HGP draft in hand, the discovery of non-protein-coding elements exploded. So far, that growth has outstripped the discovery of protein-coding genes by a factor of five, and shows no signs of slowing. Likewise, the number of publications about such elements also grew in the period covered by our data set. For example, there are thousands of papers on non-coding RNAs, which regulate gene expression.

The article also observes that prior to the Human Genome Project, which was completed in 2003, there was “great debate” over whether it was “worth mapping the vast non-coding regions of genome that were called junk DNA, or the dark matter of the genome.” Under a paradigm informed by intelligent design, debates over whether to investigate junk DNA would have ended much sooner with an emphatic Yes!, furthering our knowledge of genetics and medicine. How much sooner would these 130,000+ “genomic elements, previously called junk DNA” have been uncovered if an ID paradigm had been governing biology research? 

Sunday, May 9, 2021

Human Origins


Review: Most human origins stories are not compatible with known fossils

by American Museum of Natural History


The last common ancestor of chimpanzees and humans represents the starting point of human and chimpanzee evolution. Fossil apes play an essential role when it comes to reconstructing the nature of our ape ancestry. Credit: Printed with permission from © Christopher M. Smith

In the 150 years since Charles Darwin speculated that humans originated in Africa, the number of species in the human family tree has exploded, but so has the level of dispute concerning early human evolution. Fossil apes are often at the center of the debate, with some scientists dismissing their importance to the origins of the human lineage (the "hominins"), and others conferring them starring evolutionary roles. A new review out on May 7 in the journal Science looks at the major discoveries in hominin origins since Darwin's works and argues that fossil apes can inform us about essential aspects of ape and human evolution, including the nature of our last common ancestor.

Humans diverged from apes—specifically, the chimpanzee lineage—at some point between about 9.3 million and 6.5 million years ago, towards the end of the Miocene epoch. To understand hominin origins, paleoanthropologists aim to reconstruct the physical characteristics, behavior, and environment of the last common ancestor of humans and chimps.

"When you look at the narrative for hominin origins, it's just a big mess—there's no consensus whatsoever," said Sergio Almécija, a senior research scientist in the American Museum of Natural History's Division of Anthropology and the lead author of the review. "People are working under completely different paradigms, and that's something that I don't see happening in other fields of science."

There are two major approaches to resolving the human origins problem: "Top-down," which relies on analysis of living apes, especially chimpanzees; and "bottom-up," which puts importance on the larger tree of mostly extinct apes. For example, some scientists assume that hominins originated from a chimp-like knuckle-walking ancestor. Others argue that the human lineage originated from an ancestor more closely resembling, in some features, some of the strange Miocene apes.

In reviewing the studies surrounding these diverging approaches, Almécija and colleagues with expertise ranging from paleontology to functional morphology and phylogenetics discuss the limitations of relying exclusively on one of these opposing approaches to the hominin origins problem. "Top-down" studies sometimes ignore the reality that living apes (humans, chimpanzees, gorillas, orangutans, and hylobatids) are just the survivors of a much larger, and now mostly extinct, group. On the other hand, studies based on the "bottom-up"approach are prone to giving individual fossil apes an important evolutionary role that fits a preexisting narrative.

The positional repertoire preceding human bipedalism is unknown (so it is still in some living apes). Credit: © Sergio Almécija

"In The Descent of Man in 1871, Darwin speculated that humans originated in Africa from an ancestor different from any living species. However, he remained cautious given the scarcity of fossils at the time," Almécija said. "One hundred fifty years later, possible hominins—approaching the time of the human-chimpanzee divergence—have been found in eastern and central Africa, and some claim even in Europe. In addition, more than 50 fossil ape genera are now documented across Africa and Eurasia. However, many of these fossils show mosaic combinations of features that do not match expectations for ancient representatives of the modern ape and human lineages. As a consequence, there is no scientific consensus on the evolutionary role played by these fossil apes."

Overall, the researchers found that most stories of human origins are not compatible with the fossils that we have today.

"Living ape species are specialized species, relicts of a much larger group of now extinct apes. When we consider all evidence—that is, both living and fossil apes and hominins—it is clear that a human evolutionary story based on the few ape species currently alive is missing much of the bigger picture," said study co-author Ashley Hammond, an assistant curator in the Museum's Division of Anthropology.

Kelsey Pugh, a Museum postdoctoral fellow and study co-author adds, "The unique and sometimes unexpected features and combinations of features observed among fossil apes, which often differ from those of living apes, are necessary to untangle which features hominins inherited from our ape ancestors and which are unique to our lineage."

Living apes alone, the authors conclude, offer insufficient evidence. "Current disparate theories regarding ape and human evolution would be much more informed if, together with early hominins and living apes, Miocene apes were also included in the equation," says Almécija. "In other words, fossil apes are essential to reconstruct the 'starting point' from which humans and chimpanzees evolved."